Rapamycin has been shown to extend lifespan in numerous model organisms including mice, with the most dramatic longevity effects reported in females. However, little is known about the functional ramifications of this longevity‐enhancing paradigm in mammalian tissues. We treated 24‐month‐old female C57BL/6J mice with rapamycin for 3 months and determined health outcomes via a variety of noninvasive measures of cardiovascular, skeletal, and metabolic health for individual mice. We determined that while rapamycin has mild transient metabolic effects, there are significant benefits to late‐life cardiovascular function with a reversal or attenuation of age‐related changes in the heart. RNA‐seq analysis of cardiac tissue after treatment indicated inflammatory, metabolic, and antihypertrophic expression changes in cardiac tissue as potential mechanisms mediating the functional improvement. Rapamycin treatment also resulted in beneficial behavioral, skeletal, and motor changes in these mice compared with those fed a control diet. From these findings, we propose that late‐life rapamycin therapy not only extends the lifespan of mammals, but also confers functional benefits to a number of tissues and mechanistically implicates an improvement in contractile function and antihypertrophic signaling in the aged heart with a reduction in age‐related inflammation.

Reactive hyperemia is a well-established technique for noninvasive assessment of peripheral microvascular function and a predictor of all-cause and cardiovascular morbidity and mortality. In its simplest form, reactive hyperemia represents the magnitude of limb reperfusion following a brief period of ischemia induced by arterial occlusion. Over the past two decades, investigators have employed a variety of methods, including brachial artery velocity by Doppler ultrasound, tissue reperfusion by near-infrared spectroscopy, limb distension by venous occlusion plethysmography, and peripheral artery tonometry, to measure reactive hyperemia. Regardless of the technique used to measure reactive hyperemia, blunted reactive hyperemia is believed to reflect impaired microvascular function. With the advent of several technological advancements, together with an increased interest in the microcirculation, reactive hyperemia is becoming more common as a research tool and is widely used across multiple disciplines. With this in mind, we sought to review the various methodologies commonly used to assess reactive hyperemia and current mechanistic pathways believed to contribute to reactive hyperemia and reflect on several methodological considerations.

Peripheral artery disease (PAD) is a prevalent condition that confers substantial morbidity and mortality and remains underdiagnosed as well as undertreated in the overall population. Although PAD prevalence is similar or higher in women compared with men, associations of traditional and nontraditional risk factors with PAD and clinical manifestations of PAD differ by sex and may contribute to delayed or lack of diagnosis in women. Such sex-based differences in the manifestation of PAD may arise from sexual dimorphism in the vascular substrate in health as well as sex variation in the responses to vascular stressors. Despite the availability of proven therapies for improving symptoms and reducing risk of ischemic cardiovascular and limb events among patients with diagnosed PAD, important sex differences in treatment and outcomes have been observed. We provide an overview of current knowledge regarding sex differences in the epidemiology, pathophysiology, clinical presentation, and management of PAD.

OBJECTIVE To evaluate racial/ethnic differences in pancreatic triglyceride (TG) levels and their relationship to β-cell dysfunction in humans. RESEARCH DESIGN AND METHODS We studied black, Hispanic, and white adults who completed three research visits: screening and an oral glucose tolerance test; frequently sampled intravenous glucose tolerance tests for evaluation of β-cell function and insulin resistance; and proton magnetic resonance spectroscopy for evaluation of pancreatic and hepatic TG levels. RESULTS Pancreatic TG levels were higher in Hispanics and whites than in blacks (P = 0.006). Hepatic TG levels were highest in Hispanics (P = 0.004). Compensatory insulin secretion and disposition index were higher in blacks (P = 0.003 and P = 0.024, respectively). Insulin sensitivity was comparable between Hispanics and blacks and was lower than in whites (P = 0.005). In blacks, compensatory insulin secretion increased steeply with small increments in pancreatic TG levels (R² = 0.45, slope = 247). In whites, the range of pancreatic TG levels was higher, and the slope was less steep than in blacks (R² = 0.27, slope = 27). In Hispanics, pancreatic TG levels were similar to those of whites, but compensatory insulin secretion was described by a combination of pancreatic and hepatic TG levels and visceral fat mass ( R² = 0.32). CONCLUSIONS In a multiethnic sample of adults with mild obesity and without diabetes, we found striking ethnic differences in the levels of pancreatic TGs and in the relationship between pancreatic TGs and β-cell dysfunction. Our data implicate pancreatic TG content measured by proton magnetic resonance spectroscopy as a noninvasive novel biomarker for pancreatic β-cell dysfunction, especially in the Hispanic population.

Objective: To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD). Methods: In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil. Results: The major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD—producing functional muscle ischemia—despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD. Conclusions: These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD. Classification of evidence: This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis.